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We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions. This study aimed to investigate the protein composition of HDL particles in patients with CETP-D. Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL. We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3 ± 6.9 vs 43.7 ± 2.5, P <.001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9 ± 5.3 vs 27.1 ± 3.7, 2.3 ± 1.1 vs 0.4 ± 1.1, respectively; P <.01). We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D. • We have characterized the proteome of HDL in healthy subjects and patients with CETP-D. • We identified 79 HDL-associated proteins, 5 of which were newly identified. • ApoE, apoC-III, and complement C3 and C4b were significantly increased in HDL of CETP-D. • We identified ANGPTL3 as an HDL-associated protein, which was increased in CETP-D. • These proteomic changes might be partly responsible for atherogenicity of CETP-D. [ABSTRACT FROM AUTHOR]